CO-1 Arymo™ ER (morphine sulfate) Extended-Release Tablets for the Treatment of Chronic Pain August 4, 2016 Egalet Corporation Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee
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CO-1
Arymo™ ER (morphine sulfate) Extended-Release Tabletsfor the Treatment of Chronic Pain
August 4, 2016Egalet CorporationJoint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee
CO-2
Introduction
Robert RadiePresident and Chief Executive OfficerEgalet Corporation
CO-3
Morphine is the Most Commonly Prescribed ER Opioid in the U.S.
98.5%Non-abuse-deterrent
1.5% Abuse-deterrent
2015: 6.4 million ER morphine prescriptions
ER Morphine Prescriptions January-April 2016
IMS (National Prescription Audit) Database
CO-4
Arymo ER Provides a Broad Abuse-Deterrent Profile
Arymo ER Designed to Deter Common Routes of Abuse
ORAL(chewed / manipulated) NASAL INTRAVENOUS
• Hard tablet• Difficult to chew• Resistant to particle
size reduction and morphine extraction
• Difficult to reduce to a snortable powder
• Difficult to extract for injection
• Difficult to draw into syringe
CO-5
Guardian™ Technology Confers Physical and Chemical Barriers to Abuse
ER Profile with Physical / Chemical Abuse-deterrent Properties
• Dense, hard tablet• Resistant to particle size reduction• Resistant to chemical extraction• Prevents syringeability
Injection Molding +
Process
Polyethylene Oxide (PEO) + Morphine
Formulation
CO-6
Arymo ER was bioequivalent to MS Contin at all intended dosage strengths
Bioequivalence scientific bridge to safety and efficacy
No clinically significant food effect No evidence of alcohol dose dumping
Clinical Data Support Approval of Arymo ER
15 mg 30 mg 60 mg
CO-7
Comprehensive Abuse-Deterrent Development Program for Arymo ER
Category 1In Vitro Testing
Resistance to Physical &Chemical
Manipulation
Category 2Clinical PK Studies
PK not converted to an immediate-release
profileCmax Tmax
Category 3Clinical Abuse-
Deterrent Studies
Drug LikingTake Drug Again
Positive Drug Effects
Committed to fulfilling post-approval requirements Category 4 study to assess real-world impact of
Arymo ER on misuse and abuse
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Abuse-Deterrent Formulations ArePart of the Solution
PhysicianEducation
PrescriptionMonitoring
Abuse-Deterrent
Formulations
Patient Education
Proper Prescribing
Safe Disposal
Reduce Opioid Abuse
CO-9
Agenda
Public Health NeedRichard Dart, M.D., Ph.D.DirectorDenver Health & Hospital Authority
Abuse-Deterrent StudiesJeffrey Dayno, M.D.Chief Medical OfficerEgalet Corporation
Public Health Need for Abuse-Deterrent ER Morphine
Richard C. Dart, M.D., Ph.D.Executive Director, RADARS® SystemDirector, Rocky Mountain Poison & Drug Center Professor of Emergency Medicine, University of Colorado School of Medicine
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Particle size reduction (PSR) Defeats ER properties Releases drug faster Prepares drug for alternate routes of
Chewing has been most common manipulation in oral HAP studies
Chewing Arymo ER would not provide effective PSR and poses potential safety risk
EG-008: Oral HAP Study
Study EG-008: Oral HAP Study (N=38) Category 2 / 3
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Crushed MS Contin (60 mg) Tool B
Manipulated Arymo ER (60 mg) Tool F
Intact Arymo ER (60 mg) Placebo
Treatment Arms in Oral HAP Study Prepared by Site Pharmacy
Study EG-008: Oral HAP Study (N=38) Category 2 / 3
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Primary: Maximum (Emax) Drug Liking Secondary
Overall Drug Liking Take Drug Again Drug Effects Questionnaire
Pharmacokinetics (PK) Cmax
Tmax
AUC
Endpoints in Oral HAP Study
Study EG-008: Oral HAP Study (N=38) Category 2 / 3
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Significantly Lower Maximum Drug Liking with Manipulated Oral Arymo ER
7368
63
53
40
50
60
70
80
90
100
MS Contin,Crushed
Arymo ER,Manipulated
Arymo ER,Intact
Placebo
Mean EmaxDrug Liking
[95% CI]
p = 0.0069
Strong Liking
Disliking
Neutral
0
Study EG-008: Oral HAP Study (N=38) Category 3
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Lower Mean Drug Liking for Manipulated Arymo ER at Early Time Points
40
50
60
70
80
90
100
0 1 2 3 4
MS Contin, Crushed
Arymo ER, Manipulated
Arymo ER, Intact
Placebo
MeanDrug Liking
[95% CI]
Time (hours)
0
Strong Liking
Disliking
Neutral
AUE0-4p = 0.0008
Study EG-008: Oral HAP Study (N=38) Category 3
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Key Secondary Endpoints in Oral HAP Study
70
63
55
51
40
50
60
70
80
90
100
MS Contin,Crushed
Arymo ER,Manipulated
Arymo ER,Intact
Placebo
MeanEmax
[95% CI]
Take Drug Again
7065
5652
MS Contin,Crushed
Arymo ER,Manipulated
Arymo ER,Intact
Placebo
Overall Drug Liking
p = 0.054 p = 0.128
0
Study EG-008: Oral HAP Study (N=38) Category 3
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Significant Differences Observed in Drug High VAS and Good Effects VAS
52
39
27
5
0
20
40
60
80
100
MS Contin,Crushed
Arymo ER,Manipulated
Arymo ER,Intact
Placebo
MeanEmax
[95% CI]
Drug High
51
3526
6
MS Contin,Crushed
Arymo ER,Manipulated
Arymo ER,Intact
Placebo
Good Effects
p = 0.0035 p = 0.0025
Study EG-008: Oral HAP Study (N=38) Category 3
CO-61
Arymo ER Does Not Exhibit IR Profile after Manipulation for Oral Abuse
05
101520253035404550
0 1 2 3 4 5 6
MS Contin, CrushedArymo ER, ManipulatedArymo ER, Intact
MeanMorphine Plasma
Concentration (ng/mL)[95% CI]
Time (hours)Study EG-008: Oral HAP Study (N=38) Category 2
CO-62
Category 1 and 2/3 Development Program Support Abuse Deterrence
ORAL(chewed / manipulated)
• Difficult to chew• Met primary endpoint
for Category 2/3• All secondary PD
measures supportive• PK consistent with
PD results
NASAL
• Difficult to reduce to snortable powder
• Met primary endpoint for Category 2/3
• Statistically significant for all secondary PD measures
• PK consistent withPD results
INTRAVENOUS
• Gels in solution• Difficult to extract • Difficult to draw into
syringe
Resistant to Particle Size Reduction
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Clinical Relevance of Arymo ER Abuse-Potential Data
Nathaniel Katz, M.D., M.S.CEO, Analgesic SolutionsAdjunct Associate ProfessorTufts University School of Medicine
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Should Arymo ER be approved for the treatment of chronic pain?
Should Arymo ER be labeled as an abuse-deterrent product? IV route Nasal route Oral route (chewed / manipulated)
Two Primary Questions for Today’s Advisory Committee Meeting
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Arymo ER is bioequivalent to MS Contin No clinically significant effect of food No acceleration of release with alcohol
(i.e., no alcohol dose-dumping)
Arymo ER Has Met Regulatory Standard for Approval
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Compare route-specific laboratory results to real-world outcomes
Determine Clinically Important Difference associated with change in drug-taking behavior
Two Ways to Assess Clinical Relevance of Pre-Marketing Abuse-Deterrent Studies
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In Vitro Syringeability Findings Predict Real-World IV Abuse Deterrence
OxyContin OP
Arymo ER
“When subjected to an aqueous environment, OXYCONTIN gradually forms a viscous hydrogel (i.e., a gelatinous mass) that resists passage through a needle.”
OxyContin® Label
36%
16%
0%
10%
20%
30%
40%
50%
60%
Pre-period Post Period
Butler et al. J Pain. 2013
41%
1%0%
10%
20%
30%
40%
50%
60%
Pre-period Post Period
Havens et al. Drug Alcohol Depend. 2014
In Vitro Findings Real-world Evidence from Epidemiologic Studies
Pre-period Post-period
Pre-period Post-period
CO-68
Intranasal Human Abuse Potential Findings Predict Real-World Nasal Abuse Deterrence
53%
25%
0%10%20%30%40%50%60%
Pre-period Post Period
39%
5%
0%10%20%30%40%50%60%
Pre-period Post Period
Mean Emax Drug LikingCrushed OxyContin
(original)Crushed
OxyContin OP Difference94.0 80.4 13.6
Mean Emax Drug LikingCrushed
MS ContinManipulatedArymo ER Difference
77.7 65.5 (not sieved) 12.2
77.7 59.6 (sieved) 18.1
OxyContin OP
Arymo ER
Real-world Evidence from Epidemiologic Studies
Butler et al. J Pain. 2013
Havens et al. Drug Alcohol Depend. 2014
Intranasal HAP Studies
Pre-period Post-period
Pre-period Post-period
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Chewing is most common form of manipulated oral abuse for ER morphine*
Arymo ER hardness > 400 N Average maximum human bite force in literature
is ~300-350 N†
Arymo ER Would be Difficult or Impossible to Chew
* Inflexxion, 2015 data on file.
11%
5%
1%0%2%4%6%8%
10%12%
Chew Dissolve Drink
Prevalenceof Abuse
(%)
† Takaki et al. Int Arch Otorhinolaryngol 2014;18(3).
CO-70
Compare route-specific laboratory results to real-world outcomes
Determine Clinically Important Difference leading to change in drug-taking behavior
Two Ways to Assess Clinical Relevance of Pre-Marketing Abuse-Deterrent Studies
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8- to 10-Point Reduction in Emax Drug High is Clinically Important
Estimated clinically important difference (CID) for Emax Drug High is 8-10 mm
Eaton et al. Qual Life Res 2012;21:975-81.
CO-72
Meta-analysis of multiple human abuse potential studies across molecules
Compared to “non-medical use” (NMU) rates in NSDUH and DAWN using multiple regression
For ER morphine ADF, 5-point reduction in Emax Drug Liking predicted 20% reduction in lifetime NMU
5-Point Reduction in Emax Drug Liking is Clinically Important
White et al. J Opioid Manage 2015;11(3):199-210.NSDUH = National Survey of Drug Use and HealthDAWN = Drug Abuse Warning Network
CO-73
Arymo ER Condition
Emax Drug High Emax Drug Liking
Treatment Difference
Clinically important? (8-10 mm*)
Treatment Difference
Clinically important?
(5 mm†)NasalManipulated 33.5 Yes 12.2 Yes
NasalManipulated/sieved 45.2 Yes 18.1 Yes
Arymo ER Reductions in Drug High and Drug Liking are Clinically Important
* Eaton et al. Qual Life Res 2012;21:975-81.† White et al. J Opioid Manage 2015;11(3):199-210.
Manipulated Oral 13.1 Yes 5.0 Yes
Treatment differences in HAP studies do not reflect the fact that Arymo ER was more difficult to manipulate than MS Contin
CO-74
Totality of Data Support Broad Abuse-Deterrent Profile of Arymo ER
Intravenous• Resists small volume extraction to 24 hours
• Difficult to draw into a needle
• Difficult or impossible to chew
• Less liking than non-ADF comparator after optimal manipulation
• Low yield of particles amenable for snorting
• Less liking than non-ADF comparator Nasal
Oral
CO-75
Arymo™ ER (morphine sulfate) Extended-Release Tabletsfor the Treatment of Chronic Pain
August 4, 2016Egalet CorporationJoint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee
CO-76
Backup Slides Shown
CO-77
Large Volume Extraction –Arymo ER 60mg at 1 Hour
Category 1
0%
20%
40%
60%
80%
100%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Temperature A, Agitation B, 200 mL
Mean % Morphine
Extracted at1 Hour[SD]
Manipulated Arymo ER (Tool F -> Tool J); N=3
Solvent
OH-23
CO-78Figure 20: Morphine Extraction in Large Volumes of Ingestible and Non-Ingestible Solvents at Temperature A and Agitation B with Maximal Manipulation at 30 Minutes
BF-21
CO-79
Development Process to Identify Optimal PSR for Arymo ER
Exploratory Phase
• 25 tools• Representative of cutting, crushing, grating, grinding
Screening Phase
• 10 tools (mechanical and electrical)• MS Contin crushed to fine powder• Arymo ER tested 5 x longer to identify tools effective for Arymo ER
• MS Contin crushed to fine powder with Tool B• Does not require multi-tool process
• Arymo ER single tool result: Tool F & Tool J (< 5% particles < 500 microns)• Arymo ER challenged with sequential multi-tool procedure (F J)
• No significant changes in PSR• Increasing time resulted in plateau effect on PSR
Single- and Multi-Tool
PSR
OP-2
CO-80
0 1
10
89
14
14
82
0
10
20
30
40
50
60
70
80
90
100
<212 212-499 500-999 ≥1000
Arymo ER (Tool F)
Arymo ER (Tool F -> J)
% Particles
Particle Size
Arymo ER Particle Size Reduction:Tool F vs Tool F → J
N = 6
OD-6
CO-81
0 1
10
89
0 1
9
90
0
20
40
60
80
100
<212 212-499 500-999 ≥1000
Arymo ER 60mg (Tool F) 3 minutes N=6
Arymo ER 60mg (Tool F) 5 minutes N=3
Arymo ER Particle Size Reduction:Tool F at 3 and 5 Minutes
Mean % Particles
[SD]
Particle Size
OP-11
CO-82
0%
20%
40%
60%
80%
100%
0 2 4 6 8
Morphine Extraction from Arymo ER Over Time
Category 1
Mean % Morphine Extracted
[SD]
Solvent 5
Manipulated Arymo ER 60 mg (Tool F Tool J)
Time (hrs)0 2 4 6 8
Solvent 11
Time (hrs)
Temperature A, Agitation B, 200 ml, N=3
AA-1
CO-83
Arymo ER 60 mgSolvent 18
0%
20%
40%
60%
80%
100%
0 2 4 6 8
Mean % Morphine Extracted
[SD]
Time (hrs)Temperature A, Agitation B, 200 ml, N=3
AA-2
CO-84
Arymo ER 100 mgSolvent 18
0%
20%
40%
60%
80%
100%
0 2 4 6 8
Mean % Morphine Extracted
Time (hrs)Temperature A, Agitation B, 50 ml, N=1
AA-3
CO-85
0%
20%
40%
60%
80%
100%
Tool F → J
Arymo ER Resists Extraction in Large Volumes of Solvents 9 and 10
Solvent 9
Arymo ER 60 mg
0%
20%
40%
60%
80%
100%
Tool F → J
Category 1
Solvent 10
Temperature B, Agitation B
Mean % Morphine Extractedat 30 min
[SD]
AA-4
CO-86
0%
20%
40%
60%
80%
100%
0 2 4 6 8
Morphine Extraction from Arymo ER and MS Contin Over Time
Category 1
Mean % Morphine Extracted
[SD]
Solvent 5
Manipulated Arymo ER 60 mg (Tool F Tool J)
Crushed MS Contin 60 mg (Tool B)
Time (hrs)0 2 4 6 8
Solvent 11
Time (hrs)Temperature A, Agitation B, 200 ml, N=3 *FDA has not reviewed MS Contin data
OH-16
CO-87
Figure 31: Ease of Snorting VAS Scores in Intranasal HAP Study EG-009